A loss of mature microglial markers without immune activation in schizophrenia.

Gijsje J L J Snijders,Donald J Macintyre,Marjolein A M Sneeboer,Amber Berdenis Van Berlekom,Elly M Hol,Astrid T Van Der Geest,Lot D De Witte,Welmoed Van Zuiden,René S Kahn,Tatiana Schnieder

doi:10.1002/glia.23962

Abstract

Microglia, the immune cells of the brain, are important for neurodevelopment and have been hypothesized to play a role in the pathogenesis of schizophrenia (SCZ). Although previous postmortem studies pointed toward presence of microglial activation, this view has been challenged by more recent hypothesis‐driven and hypothesis‐free analyses. The aim of the present study is to further understand the observed microglial changes in SCZ. We first performed a detailed meta‐analysis on studies that analyzed microglial cell density, microglial morphology, and expression of microglial‐specific markers. We then further explored findings from the temporal cortex by performing immunostainings and qPCRs on an additional dataset. A random effect meta‐analysis showed that the density of microglial cells was unaltered in SCZ (ES: 0.144 95% CI: 0.102 to 0.390, p = .250), and clear changes in microglial morphology were also absent. The expression of several microglial specific genes, such as CX3CR1, CSF1R, IRF8, OLR1, and TMEM119 was decreased in SCZ (ES: −0.417 95% CI: −0.417 to −0.546, p < .0001), consistent with genome‐wide transcriptome meta‐analysis results. These results indicate a change in microglial phenotype rather than density, which was validated with the use of TMEM119/Iba1 immunostainings on temporal cortex of a separate cohort. Changes in microglial gene expression were overlapping between SCZ and other psychiatric disorders, but largely opposite from changes reported in Alzheimer's disease. This distinct microglial phenotype provides a crucial molecular hallmark for future research into the role of microglia in SCZ and other psychiatric disorders.

Highlights

Genetic and epidemiological studies have suggested a causal role for the immune system in schizophrenia (SCZ) pathogenesis (Benros et al, 2014; Pouget et al, 2019; Ripke et al, 2014; Sekar et al, 2016; van Mierlo, Schot, Boks, & de Witte, 2019)
When segregating the analysis per brain regions, we found a significant increase in microglial density in the temporal cortex (ES: 2.27 95% CI: 1.469–3.090, p < .001, Q-between = 29.72; p < .001) in SCZ patients, but this was not observed in the other brain regions
The aim of the present study was to provide an update of the microglial changes that have been found in postmortem brain tissue of patients with SCZ

Summary

Introduction

Genetic and epidemiological studies have suggested a causal role for the immune system in schizophrenia (SCZ) pathogenesis (Benros et al, 2014; Pouget et al, 2019; Ripke et al, 2014; Sekar et al, 2016; van Mierlo, Schot, Boks, & de Witte, 2019). Upthegrove, Manzanares-Teson, & Barnes, 2014; Wang & Miller, 2018) It has, been hypothesized that microglia, the immune cells of the brain, play an important role in SCZ (Howes & McCutcheon, 2017). Copy number variants in complement factor 4A (C4A) are associated with SCZ (Sekar et al, 2016), and increased synaptic pruning was observed in patientderived microglial cell cultures (Sellgren et al, 2019)

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Conclusion